1. Field of the Invention
This invention relates generally to radioiodinated compounds which are useful as radiopharmaceuticals, and more specifically, to radioiodinated arylaliphatic cholesteryl ether analogues of naturally-occurring cholesteryl esters which exhibit specificity for low density lipoproteins and are useful, inter alia, for scintigraphic imaging of adrenal glands and as biological probes for lipoprotein research.
2. Prior Art
Since the ester linkage of naturally-occurring cholesteryl esters is quickly hydrolyzed in vivo, cholesteryl ester analogues which are resistant to hydrolysis upon administration to animals or humans would be of significant value to researchers in quantitating cholesteryl ester uptake into tissues. Currently available cholesteryl ether compounds which are marketed for research purposes are radio-tagged with tritium (.sup.3 H). However, tritium emissions are of the weak beta type. In fact, the emission is so weak that tissue samples, for example, must be concentrated in vitro to faciliate detection. Equipment for detecting beta emission is required to be highly sensitive, and therefore costly. Thus, the use of beta-emissive marker compounds is problematical, even in a laboratory situation. For in vitro work, the gamma-emitting isotopes of iodine, particularly .sup.125 I, are the isotopes of choice.
The use of tritiated agents in in vivo applications has the further disadvantage that any intersecting structure, such as adjacent tissue, will completely absorb, or substantially mask, the emission before the tritium can be detected. Radiolabelling cholesteryl ester analogues with the gamma-emitting isotopes of iodine (particularly, .sup.123 I and .sup.131 I could be used to produce potentially useful scintigraphic imaging agents. There are currently available no radioiodinated analogues of naturally-occurring cholesteryl esters. Of particular interest would be scintigraphic agents which would be useful for detecting problems associated with, inter alia, coronary artery disease, adrenal dysfunction, and cancerous tumors.
Radioiodinated cholesterol analogues are currently in use for adrenal imaging. One known compound, a free norcholesterol, is marketed under the designation NP-59. NP-59 is chemically named 6-b-iodomethyl-19-norcholest-5[10]en-3b-ol, the uptake of which into the adrenal glands is extremely slow. In fact, it takes about five days to image the adrenal glands following administration of the imaging agent. Therefore, NP-59 is radiolabelled with .sup.131 I due to its long half-life. Thus, the radiation dose to the subject is high. Moreover, NP-59 is subject to metabolic loss of iodine and resulting accumulation of this iodine in the thyroid. There is, thus, a great need for a radiologic agent which is stable, non-metabolizable, inexpensive to produce and which can be administered to the subject with a low dosage of radioactivity.
There is additionally a need for a marker for low density lipoproteins (LDL). Low density lipoproteins are a cause atherosclerosis. There are not currently available any imaging agents for visualizing atherosclerotic lesions in vivo. Thus, a compound which can be radiolabelled and would be selectively localized in low density lipoproteins would be useful in the detection of coronary artery disease.
It is, therefore, an object of this invention to provide a radiopharmaceutical for gamma camera scintigraphy.
It is another object of this invention to provide a radio-pharmaceutical for selective visualization of, inter alia, adrenal glands, endocrine tumors, and atherosclerotic lesions.
It is also an object of this invention to provide a radiopharmaceutical which represents an improvement in terms of dosage requirement and rapidity of uptake over currently available agents.
It is a further object of this invention to provide radioiodinated analogues of naturally-occurring cholesteryl esters which are non-hydrolyzable upon administration to a human or animal.
It is additionally an object of this invention to provide radioiodinated arylaliphatic cholesteryl ether analogues of naturally-occurring cholesteryl esters which exhibit specificity for low density lipoproteins.
It is yet further object of this invention to provide a radioiodinated arylaliphatic cholesteryl ether analogues of naturally-occurring cholesteryl esters which are stable, non-metabolizable, inexpensive to produce, and which can be administered to the subject with a low dosage of radioactivity.